Guarise, Cristian (2008) Sintesi su fase solida, valutazione catalitica e di riconoscimento molecolare di sistemi tripodali. [Tesi di dottorato]
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Solid phase synthesis of tripodal systems and study of their catalytic and molecular recognitions properties
Tripodal molecular structures are increasingly applied in the fields of catalysis, recognition, sensing, and biomimetics. The problem is that the combinatorial approach, that gives access to large amounts of heterofunctionalized receptors, uses orthogonally protected scaffolds and requires a very laborious synthesis. In this research project, a versatile synthetic approach for the functionalization of tripodal scaffold molecules on solid support, was developed. The generality of this approach was illustrated by the functionalization of three structurally diverse A3-type scaffold molecules containing multiple amino-groups (1a, 1,3,5-tris(aminoethyl)-2,4,6-triethylbenzene; 1b, tris(2-aminoethyl)amine; 1c, triazacyclononane) with a variety of different functional groups. Advantages of this approach are its simplicity and the freedom to functionalise any desirable scaffold molecule, without the use of protecting groups or special functionalisation patterns (for instance AB3). Intrinsic problems related to the attachment of tripodal scaffolds to a resin (for example mono- versus polyadducts and intramolecular cyclizations) were studied and solutions were provided. Importantly, protecting groups on the scaffold molecule were never used, which significantly facilitates scaffold variation, for instance for combinatorial studies.
The synthetic approach was used in order to obtain multivalent C3-symmetrical molecules as artificial models of enzymes catalytic site. The general goal was to understand whether the scaffold structure influenced the cooperativity between the functional groups.
First, we have synthesized an artificial model of a serine protease (or esterase), by connecting to scaffold 1a different combinations of peptides, based on the amino acids of the active site of the proteolytic enzyme: Asp, His and Ser. Studies of these compounds in the hydrolysis of activated esters revealed catalytic activity for the scaffold 1a functionalized with the active sequence -CO-Asp-His-H.
Subsequently, we have functionalized a Calixarene scaffold with the same active sequence for which a significant 86-fold rate enhancement compared to that of the uncatalyzed background reaction has been observed. This study showed cooperativity between the functional groups only in the hydrolysis reactions performed with excess of catalyst, likely because the catalyst does not provide a well defined active site. Second, a tripodal scaffold functionalized with the -CO-Asp-Pro-Pro-H sequence, active in aldol asymmetric condensations, has been studied. Catalytic studies, performed with excess of catalyst, show that also for this catalyst the presence of the scaffold does not result in an increase in the enantioselectivity with respect to the monomeric unit. In these tripodal catalysts show a prevailing divergent structure that does not allow high cooperativity between the functional groups. Consequently we shifted our attention to tripodals structures for application in the field of molecular (bio)recognition.
For this purpose, we have chosen to study multivalent HIV-1 fusion inhibitors based on small 310-helical foldamers.
HIV-1 entry into target cells is a multistep process involving a series of proteins and cofactors. Glycoproteins gp41, decorating in the surface of HIV-1 play key roles in this process. The ectodomain (extraviral) of gp41 consists of three important regions: an N-terminal fusion sequence that inserts into the target cell membrane, and two helical regions containing two hydrophobic heptad repeat units (denoted as the N- and C-helical regions, respectively). The N-HR regions of three gp41 molecules form a trimeric ?-helical coiled-coil. Upon dissociation of gp120 from the complex, a six-helix bundle forms, in which the C-helical regions wrap around the inner coil in an antiparallel fashion. We have studied a series of strategies for the synthesis of small peptide inhibitors, based on small 310-helical foldamers. These molecules have been designed for the inhibition of HIV-1 replication by binding to the inner trimeric coiled coil, thus preventing the formation of the six-helix bundle, which is essential for the complete fusion of the virus to target cell membranes.
The 310-helix conformation is induced with the introduction of 5 Aib-residues in the peptide inhibitor sequence. In that way the amino acids Trp, Trp, and Ile (the WWI epitope) of the peptide are placed in the same positions of the N-HR helix regions of gp41 molecules. Currently we are studying a synthetic strategy in order to covalently link this foldamer to a tripodal scaffold (with oligoPEG spacers).
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